Stereotyped paroxysmal psychiatric symptoms during oculogyric crisis or 'cognitive dystonia': a case report

Oculogyric crisis (OGC) is an acute dystonia which can occur after initiation of antipsychotic treatment. Stereotypic paroxysmal psychiatric symptoms have been described along with OGC that resolve spontaneously when the later remits. We report a case of tardive OGC associated with zuclopenthixol in which there were associated paroxysmal auditory pseudohallucinations.     

Three cases of improvement of tardive dyskinesia following olanzapine treatment

To date, clozapine is the only antipsychotic agent that has established itself as having minimal, if any, risk of tardive dyskinesia (TDk). In patients with TDk, clozapine permits the dyskinesia to disappear in approx. 50% of cases, particularly those with dystonic features, i.e. tardive dystonia (TDt) (Gardos, 1999). Unfortunately, clozapine is not always efficacious. Furthermore, some patients cannot be treated with clozapine because of its side-effects. Olanzapine is a serotonin-dopamine-receptor antagonist, which has an affinity for neuroreceptors similar to that of clozapine. Pooled tolerability data from controlled trials show that the overall incidence of TDk in patients treated with olanzapine is significantly lower than in patients treated with haloperidol (Tollefson et al., 1997). Here, we report three cases of patients affected by tardive disorders who dramatically improved after olanzapine treatment.     

Extrapyramidal symptoms with atypical antipsychotics : incidence, prevention and management.

The treatment of schizophrenia changed drastically with the discovery of antipsychotic medications in the 1950s, the release of clozapine in the US in 1989 and the subsequent development of the atypical or novel antipsychotics. These newer medications differ from their conventional counterparts, primarily based on their reduced risk of extrapyramidal symptoms (EPS). EPS can be categorised as acute (dystonia, akathisia and parkinsonism) and tardive (tardive dyskinesia and tardive dystonia) syndromes. They are thought to have a significant impact on subjective tolerability and adherence with antipsychotic therapy in addition to impacting function. Unlike conventional antipsychotic medications, atypical antipsychotics have a significantly diminished risk of inducing acute EPS at recommended dose ranges. These drugs may also have a reduced risk of causing tardive dyskinesia and in some cases may have the ability to suppress pre-existing tardive dyskinesia. This paper reviews the available evidence regarding the incidence of acute EPS and tardive syndromes with atypical antipsychotic therapy. Estimates of incidence are subject to several confounds, including differing methods for detection and diagnosis of EPS, pretreatment effects and issues surrounding the administration of antipsychotic medications. The treatment of acute EPS and tardive dyskinesia now includes atypical antipsychotic therapy itself, although other adjunctive strategies such as antioxidants have also shown promise in preliminary trials. The use of atypical antipsychotics as first line therapy for the treatment of schizophrenia is based largely on their reduced risk of EPS compared with conventional antipsychotics. Nevertheless, EPS with these drugs can occur, particularly when prescribed at high doses. The EPS advantages offered by the atypical antipsychotics must be balanced against other important adverse effects, such as weight gain and diabetes mellitus, now known to be associated with these drugs.     

Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management

Long-term administration of antipsychotics occasionally produces persistent dystonia of the trunk, a disorder known as Pisa syndrome (or pleurothotonus). The development of Pisa syndrome is most commonly associated with prolonged treatment with antipsychotics; however, it has also been reported, although less frequently, in patients who are receiving other medications (such as cholinesterase inhibitors and antiemetics), in those not receiving medication (idiopathic Pisa syndrome) and in those with neurodegenerative disorders. Drug-induced Pisa syndrome predominantly develops in females and in older patients with organic brain changes. It sometimes occurs after the addition of another antipsychotic to an established regimen of antipsychotics or insidiously arises in antipsychotic-treated patients for no apparent reason. The condition generally disappears after antipsychotic drugs are discontinued. Although a pharmacological therapy for drug-induced Pisa syndrome has not been established, we have reported that anticholinergic drugs are effective in about 40% of patients who have episodes of Pisa syndrome with the remaining patients responding to the withdrawal or reduction of daily doses of antipsychotic drugs. The characteristics of its development and prognosis indicate that drug-induced Pisa syndrome consists of two types of dystonia. Some patients develop clinical features of acute dystonia, whereas others develop symptoms similar to tardive dystonia. Like that of tardive dystonia, Pisa syndrome responds better than tardive dyskinesia to a relatively high daily dose of an anticholinergic. However, the significant improvement caused by the withdrawal of antipsychotic drugs in Pisa syndrome differentiates it from tardive dystonia. Thus, Pisa syndrome including these features is considered to be an atypical type of tardive dystonia. These clinical characteristics suggest that the underlying pathophysiology of drug-induced Pisa syndrome is complex. A dopaminergic-cholinergic imbalance, or serotonergic or noradrenergic dysfunction, may be implicated. Asymmetric brain functions or neural transmission may also be considered as underlying mechanisms of the development of Pisa syndrome that is resistant to anticholinergic drugs. Idiopathic Pisa syndrome is characterised by an adult-onset, segmental truncal dystonia in patients with no previous exposure to antipsychotics. It occurs rarely but shows a complete resolution with high doses of anticholinergic drugs.     

Extrapyramidal syndromes in nonhuman primates: typical and atypical neuroleptics.

The traditional (typical) neuroleptic drugs produce acute extrapyramidal symptoms (EPS) in the majority of patients, whereas the atypical neuroleptics produce only minimal motor system side effects. Studies of acute dystonia in nonhuman primates with typical (haloperidol, fluphenazine), atypical (clozapine), and putative novel antipsychotic compounds with low EPS (remoxipride, melperone) were conducted across a wide dose range in double-blind, placebo-controlled trials. Haloperidol and fluphenazine caused dystonia, and clozapine did not. Remoxipride and melperone also produced dystonia, but remoxipride only did so at doses that were higher than needed for antipsychotic efficacy. Melperone produced dystonia in doses that are in the antipsychotic dose range. The clinical relevance of the findings is discussed.     

Seroquel: behavioral effects in conventional and novel tests for atypical antipsychotic drug

Seroquel was compared to clozapine and several other antipsychotic agents in tests predictive of antipsychotic activity or extrapyramidal symptoms. In the conditioned avoidance test in squirrel monkeys as well as several paradigms using apomorphine or amphetamine-induced behavioral alterations, seroquel displayed the profile of a drug with potential antipsychotic activity. In these paradigms the potency of seroquel was somewhat less than clozapine in rodent tests, while the reverse was true in higher species, i.e. monkeys, cats. In tests designed to evaluate the propensity to induce EPS or tardive dyskinesia, for example, the production of dyskinetic reactions in haloperidol-sensitized cebus monkeys, seroquel displayed a profile similar to clozapine and disparate from typical antipsychotic drugs. In drug-naive cebus monkeys seroquel sensitized significantly fewer monkeys than haloperidol and the dyskinetic reactions were of significantly less intensity. It is anticipated that this novel antipsychotic agent will have a significantly reduced propensity to produce extrapyramidal symptoms and tardive dyskinesia than typical antipsychotics.     

Effect of clozapine in severe tardive dyskinesia: a case report

There have been conflicting reports as to whether clozapine, an atypical antipsychotic, will suppress symptoms of tardive dyskinesia. With this in mind, the authors present the case of a 32-year-old chronically institutionalized schizophrenic who showed a remarkable improvement in both tardive dyskinesia and psychotic symptoms following an open trial of clozapine, 900 mg daily. This effect was noted to persist throughout the 15-month observation period with no breakthrough dyskinesia. The ability of clozapine to suppress tardive dyskinesia symptoms raises the possibility that clozapine, at least at the doses used in this report, might also induce the disorder. Long-term, controlled studies are required to specifically address this issue.     

Managing antipsychotic-induced tardive dyskinesia.

Antipsychotic-induced tardive dyskinesia is a common and clinically significant hazard of long term antipsychotic therapy. The arrival of atypical antipsychotics has markedly improved the outlook: atypical antipsychotics are emerging as effective treatments and may also reduce the prevalence and incidence of tardive dyskinesia. In mild cases, careful monitoring of tardive dyskinesia by serial Abnormal Involuntary Movements Scale (AIMS) assessments may be the appropriate course. More severe tardive dyskinesia calls for intervention in order to treat the dyskinesia. Atypical antipsychotics and tocopherol (vitamin E) are effective and generally well tolerated treatment options for tardive dyskinesia. Tardive dyskinesia variants such as tardive dystonia and tardive akathisia tend to be more severe and difficult to treat compared with typical tardive dyskinesia. Prevention of tardive dyskinesia is possible through careful selection of patients for antipsychotic therapy, use of the lowest effective antipsychotic dosages, use of atypical rather than traditional antipsychotics and concurrent tocopherol administration. The clinician can now undertake the management of tardive dyskinesia with growing confidence.     

Biochemical and behavioural properties of clozapine

The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.     

Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenic patients

8 male schizophrenic patients participated in a double-blind, cross over study of the extrapyramidal side-effects of haloperidol and clozapine (acute dystonia, Parkinsonism and tardive dyskinesia), together with their effect on homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF). Haloperidol (9 mg/day) caused Parkinsonism, reduced tardive dyskinesias and increased the HVA concentration in the CSF. Clozapine (225 mg/day) had no effect on the neurological phenomena but reduced HVA and 5-HIAA concentrations in the CSF. During the discontinuation phase following the administration of haloperidol, tardive dyskinesia occurred or was aggravated; this did not occur after administration of clozapine. Accordingly, it is suggested that clozapine does not induce dopaminergic hypersensibility and, therefore, will not induce tardive dyskinesias.Part of this work was presented at the 9th C.I.N.P. Congress, Paris, July 7–12, 1974.     

Antipsychotic drugs in bipolar disorder

Antipsychotic drugs are useful in the treatment of acute mania and as maintenance treatment. While both typical and atypical antipsychotic drugs are able to diminish manic symptoms, agitation and aggression in acute mania, the atypical antipsychotic drugs enjoy a number of advantages, including significantly less extrapyramidal symptoms, diminished risk of tardive dyskinesia, lack of increase in serum prolactin levels (with the exception of risperidone), improvement in cognition, and possible decrease in suicidality. Most of the atypical antipsychotic drugs have been found to be effective as an add-on treatment (with mood stabilizers and antidepressant drugs) and sometimes as monotherapy in treatment-resistant bipolar patients. Long-acting typical neuroleptic drugs may be useful in the treatment of non-compliant bipolar patients. A small number of patients with schizophrenia treated with risperidone, olanzapine, or quetiapine experience a first episode of hypomania or mania. It is not apparent if this is a true drug-induced event or coincidental. Side-effects of note with the atypical antipsychotic drugs are weight gain (most prominently with olanzapine and clozapine), sedation, and agranulocytosis (clozapine). Atypical antipsychotic drugs are recommended for use in bipolar disorder for acute treatment, maintenance treatment, and for treatment-resistant patients.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations

We reviewed the epidemiological aspects of antipsychotic-induced movement disorders as they pertain to older patients. The incidence and prevalence of drug-induced parkinsonism and tardive dyskinesia (TD) are significantly greater in the older patient than in the younger patient whereas akathisia seems to occur evenly across the age spectrum and dystonia is uncommon among older patients. The literature on risk factors associated with treatment-emergent movement disorders is highly variable. Treatment practices vary across the age range and the interaction between age and antipsychotic dosage confounds our understanding of the relative importance of treatment-related risk factors. However, there is general agreement that pre-existing extrapyramidal signs (EPS) increase the vulnerability of the patient to developing significant drug-induced movement disorders. Elderly patients with dementia are at greater risk than patients without dementia for persistent drug-induced EPS. Management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics and beta-blockers. At present, well-controlled double-blind studies of second-generation antipsychotics such as clozapine, risperidone. olanzapine or quetiapine for reducing the risk of treatment-emergent movement disorders in the elderly have not been published. However, open-label studies of atypical antipsychotics demonstrate a markedly lower incidence of both EPS and TD compared with conventional antipsychotic treatment in the elderly. There is emerging literature in support of atypical antipsychotics for the treatment of existing drug-induced movement disorders. More controversial is the use of adjunctive antioxidants in newly treated patients who are vulnerable to drug-induced movement disorders. While the evidence is mixed in support of antioxidants for the treatment of TD, the possibility remains that prophylactic use of antioxidants may help reduce the incidence of TD. The development of a drug-induced movement disorder often reduces the quality of life in an elderly patient. Effective pharmacological management requires cooperation from the patient and family, which can be fostered early in the patient's care through proper informed consent. The risks and benefits of antipsychotic treatment in the elderly patient need to be communicated to the patient and family. At the present time, there is no consistently effective treatment for patients with TD once it develops. Therefore, attention should focus on its prevention and close monitoring.     

Clozapine in tardive dyskinesia

Clozapine, which has had limited clinical testing in the U.S.A., was evaluated in 12 chronic schizophrenic patients with tardive dyskinesia. Its antipsychotic activity was again demonstrated and it suppressed the symptoms of tardive dyskinesia with a marked rebound occurring in these symptoms when it was withdrawn; there was no rigidity or other Parkinsonian symptoms. However, out of a total of 12 patients, neutropenia (800 and 1120) occurred in two patients, convulsions in one patient, marked withdrawal effects in three patients, and a hypotensive collapse with atrial fibrillation in one patient. If these adverse effects are confirmed in a larger sample size, then despite the novel desirable effects of clozapine it would seem unlikely that it will gain widespread or routine use¹.     

The new generation of antipsychotic drugs: how atypical are they?

The cardinal feature of traditional neuroleptic drugs is extrapyramidal symptoms (EPS), such as parkinsonism, akathisia, and dystonia. Irrespective of the autonomic nervous system side-effect profile of a specific neuroleptic, the entire class produces EPS. Therefore, EPS and antipsychotic activity were once thought to be inextricably linked. However, with the discovery of clozapine, this concept was no longer defensible. Clozapine produced antipsychotic actions without associated EPS or increases in serum prolactin levels, and the term 'atypical' was coined to differentiate its actions from those of the traditional agents. Later, the definition of atypical was expanded to encompass clozapine's unique clinical spectrum of activity, including its effectiveness in treating some patients unresponsive to traditional neuroleptics. Clozapine thus became the archetype for a new generation of antipsychotic drugs, which now includes quetiapine, olanzapine, risperidone, sertindole, ziprasidone, zotepine and amisulpride. This paper will review the pharmacological actions that contribute to the unique features of clozapine, focusing on receptor profile and activity in animal models used for evaluations of antipsychotic activity and EPS. Similarities and differences amongst the new agents will also be discussed. Although conclusions regarding atypicality require controlled clinical trials in addition to preclinical and animal models, it is apparent from this review that not all agents match the profile of clozapine.     

The effect of clozapine on caudate nucleus volume in schizophrenic patients previously treated with typical antipsychotics.

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.     

Selective modulation of fibroblast growth factor-2 expression in the rat brain by the atypical antipsychotic clozapine.

In the present paper we investigated, in the rat brain, the expression of basic fibroblast growth factor (FGF-2) in response to the atypical antipsychotic clozapine. We found that acute or chronic administration of this compound produced a selective increase of FGF-2 mRNA and protein in the striatum. Although acute injection of clozapine did increase FGF-2 expression in parietal cortex and nucleus accumbens we found that, following repeated administration, the induction of the trophic molecule was taking place only at striatal level. The analysis of other antipsychotic drugs did not provide conclusive evidence for the molecular mechanisms involved in clozapine-induced elevation of FGF-2. In fact, chronic administration of classical neuroleptics, haloperidol and chlorpromazine, did not alter the expression of FGF-2. Furthermore the novel drugs quetiapine and olanzapine, despite some similarities in their receptor profiles, were similarly ineffective. Hence these data suggest that, among antipsychotic drugs, the induction of FGF-2 is unique to clozapine. On the basis of the neuroprotective activity of this trophic molecule, our data might be relevant for the potential use of clozapine in tardive dyskinesia and parkinsonism, which develop during long term administration of classical neuroleptic drugs.     

Treatment with the new antipsychotic sertindole for late-occurring undesirable movement effects

Conventional antipsychotics are often associated with late-occurring undesirable movement effects. To gain more experience with newer antipsychotic agents, 151 patients in an acute admissions department were switched from treatment with conventional antipsychotics to sertindole between late 1996 and early 1998. Four of these patients had tardive dyskinesia, tardive dystonia and/or tardive akathisia. The effect of changing to sertindole was measured using specific rating scales for undesirable movement effects. Three of the four patients apparently recovered from the movement disorders after switching to sertindole. In one patient, sertindole monotherapy was not sufficient to reduce the movement effects, but combination treatment with tetrabenazine resulted in a greater reduction in extrapyrimidal symptoms. Because these are case reports, no direct conclusions can be drawn. However, the beneficial effect of sertindole on severe, late-occurring movement disorders, as observed in four difficult-to-treat patients, appears to be promising.     

Clozapine pre-treatment enhances raclopride catalepsy.

The clinical replacement of clozapine by another antipsychotic sometimes causes extrapyramidal signs, including dystonia, to appear suddenly. The present study was done, therefore, to test whether clozapine pre-treatment of rats could affect raclopride-induced catalepsy. Clozapine, at 5 mg/kg, given 2 h before a catalepsy-threshold dose of 0.1 mg/kg raclopride, markedly enhanced raclopride-induced catalepsy in the rats. The results are compatible with earlier in vitro data where pre-exposure of human cloned dopamine D2 receptors to clozapine resulted in an increased potency of raclopride in inhibiting the binding of [3H]clozapine to the receptors. The mechanism of clozapine potentiation of raclopride action may contribute to the clinically observed post-clozapine dystonia.